Appropriateness of Acid Suppression Therapy.

BACKGROUND: The inappropriate startup of long-term acid suppressive therapy (AST) can have clinical and pharmacoeconomic impacts on ambulatory care. OBJECTIVE: To assess the proportion of patients with appropriate initiation of long-term AST in non-critically ill patients. To describe possible risk factors for nonappropriate AST. To calculate the potential savings when eliminating the nonappropriate startup of AST. METHOD: This observational, retrospective study evaluated the appropriateness of startup of long-term AST in medical records using a broad variety of international criteria and guidelines and using a validated screening instrument. RESULTS: A sample of 597 patients was included in the analysis. In 57% of them, AST was appropriately initiated. No specific risk profile could be defined. There was some indication that the availability of a clinical pharmacist and the use of standing orders were correlated to the outcome. Extrapolation to the total population (ie, 2836 patients) led to a total cost of €8880 during hospital stay plus an extra €40 391 per month after discharge. Avoiding inappropriate initiation of AST could lead to a saving of €3805 plus €17 441 per month. CONCLUSION: In all, 43% of initiation of long-term AST in the hospital was inappropriate. The potential savings from avoiding this could be substantial from a health care payer perspective. No patient characteristics that could predict for inappropriate initiation of AST were identified. A correlation between inappropriate initiation and medical disciplines using standing orders that include AST was seen.

Predictors for unintentional medication reconciliation discrepancies in preadmission medication: a systematic review.

PURPOSE: Discrepancies in preadmission medication (PAM) are common and potentially harmful. Medication reconciliation is able to reduce the discrepancy rate, yet implementation is challenging. In order for reconciliation efforts to be more cost-effective, patients at high risk for reconciliation errors should be identified. The purpose of this systematic review is to identify predictors for unintentional discrepancies in PAM. METHODS: Medline and Embase were searched systematically until June 2017. Only studies concerning adult subjects were retained. Quantitative studies were included if predictors for unintentional discrepancies in the PAM had been determined on hospital admission. Variables were divided into patient-, medication-, and setting-related predictors based on a thematic analysis. Studies on identification of predictors for discrepancies and potentially harmful discrepancies were handled separately. RESULTS: Thirty-five studies were eligible, of which 5 studies focused on potentially harmful discrepancies. The following 16 significant variables were identified using multivariable prediction models: number of preadmission drugs, patient's age, availability of a drug list, patients' understanding of medication, usage of different outpatient pharmacies, number of high-risk drugs, discipline for which the patient is admitted, admitting physician's experience, number and type of consulted sources, patient's gender, type of care before admission, number of outpatient visits during the past year, class of medication, number of reimbursements, use of an electronic prescription system, and type of admission (elective vs emergency). The number of preadmission drugs was identified as a predictor in 20 studies. Potentially harmful discrepancies were ascertained in 5 studies with age found to have a predictive value in all 5 studies. CONCLUSION: Multiple suitable predictors for PAM-related discrepancies were identified of which higher age and polypharmacy were reported most frequently.

Developing a decision rule to optimise clinical pharmacist resources for medication reconciliation in the emergency department.

BACKGROUND: The process of obtaining a complete medication history for patients admitted to the hospital from the ED at hospital admission, without discrepancies, is error prone and time consuming. OBJECTIVES: The goal of this study was the development of a clinical decision rule (CDR) with a high positive predictive value in detecting ED patients admitted to hospital at risk of at least one discrepancy during regular medication history acquisition, along with favourable feasibility considering time and budget constraints. METHODS: Data were based on a previous prospective study conducted at the ED in Belgium, describing discrepancies in 3592 medication histories. Data were split into a training and a validation set. A model predicting the number of discrepancies was derived from the training set with negative binomial regression and was validated on the validation set. The performance of the model was assessed. Several CDRs were constructed and evaluated on positive predictive value and alert rate. RESULTS: The following variables were retained in the prediction model: (1) age, (2) gender, (3) medical discipline for which the patient was admitted, (4) degree of physician training, (5) season of admission, (6) type of care before admission, number of (7) drugs, (8) high-risk drugs, (9) drugs acting on alimentary tract and metabolism, (10) antithrombotics, antihaemorrhagics and antianaemic preparations, (11) cardiovascular drugs, (12) drugs acting on musculoskeletal system and (13) drugs acting on the nervous system; all recorded by the ED physician on admission. The final CDR resulted in an alert rate of 29% with a positive predictive value of 74%. CONCLUSION: The final CDR allows identification of the majority of patients with a potential discrepancy within a feasible workload for the pharmacy staff. Our CDR is a first step towards a rule that could be incorporated into electronic medical records or a scoring system.

Plasmalyte: No Longer a Culprit in Causing False-Positive Galactomannan Test Results.

False-positive galactomannan (GM) results have been reported in patients treated with gluconate-containing solutions, such as Plasmalyte. The GM optical density index was tested on 33 distinct batches of Plasmalyte and was found to be negative in all of the batches, confirming that Plasmalyte is no longer a cause of false-positive GM results.

Pharmacokinetic profile of voriconazole in a critically ill patient on therapeutic plasma exchange.

BACKGROUND: Extracorporeal removal of drugs during therapeutic plasma exchange (TPE) can lead to decreased efficacy, as shown in several reports discussing altered pharmacokinetics (PKs) of antibiotics during TPE. In particular, drugs with a low volume of distribution or a high protein binding are susceptible to extracorporeal removal, as these drugs remain substantially within the intravascular space. No information is known about antifungal drug removal during TPE. We report the PKs of voriconazole in a critically ill patient undergoing TPE. METHODS: A 61-year-old man, presenting with catastrophic antiphospholipid syndrome for which TPE was started, developed probable pulmonary invasive aspergillosis. Intravenous voriconazole was started. Blood samples were taken under steady state conditions to calculate PK parameters of voriconazole, both with and without TPE. RESULTS: PK parameters (area under the curve, Cl, Vd, and t1/2) were equivalent on both days. Voriconazole has a distribution volume of 4.5 L/kg and a protein binding of 58%, suggesting that drug removal during TPE would not be clinically significant. Our data support this assumption. CONCLUSION: Based on our findings, it seems that TPE does not alter the PK behavior of voriconazole. Voriconazole dosages should not be adjusted during TPE.

Quality of care for cancer patients on home parenteral nutrition: development of key interventions and outcome indicators using a two-round Delphi approach.

PURPOSE: Clear recommendations on how to guide patients with cancer on home parenteral nutrition (HPN) are lacking as the use of HPN in this population remains a controversial issue. Therefore, the aims of this study were to rank treatment recommendations and main outcome indicators to ensure high-quality care and to indicate differences in care concerning benign versus malignant patients. METHODS: Treatment recommendations, identified from published guidelines, were used as a starting point for a two-round Delphi approach. Comments and additional interventions proposed in the first round were reevaluated in the second round. Ordinal logistic regression with SPSS 2.0 was used to identify differences in care concerning benign versus malignant patients. RESULTS: Twenty-seven experts from five European countries completed two Delphi rounds. After the second Delphi round, the top three most important outcome indicators were (1) quality of life (QoL), (2) incidence of hospital readmission and (3) incidence of catheter-related infections. Forty-two interventions were considered as important for quality of care (28/42 based on published guidelines; 14/42 newly suggested by Delphi panel). The topics 'Liver disease' and 'Metabolic bone disease' were considered less important for cancer patients, together with use of infusion pumps (p = 0.004) and monitoring of vitamins and trace elements (p = 0.000). Monitoring of QoL is considered more important for cancer patients (p = 0.03). CONCLUSION: Using a two-round Delphi approach, we developed a minimal set of 42 interventions that may be used to determine quality of care in HPN patients with malignancies. This set of interventions differs from a similar set developed for benign patients.

Augmented renal clearance in the critically ill: how to assess kidney function.

BACKGROUND: Augmented renal clearance in critically ill patients can result in underdosing of life-saving drugs, potentially leading to therapeutic failure. To detect this phenomenon, correct assessment of the kidney function is essential. Currently, little is known about the validity of mathematical formulas to estimate renal function in this subset of patients. OBJECTIVE: To evaluate the validity of different methods to estimate kidney function in critically ill patients with augmented renal clearance by comparing measured renal clearance with estimated clearance using different formulas. METHODS: An observational, retrospective, single-center study was conducted in a 34-bed surgical intensive care unit (SICU) of the University Hospitals Leuven, Leuven, Belgium. Adults admitted to the SICU in 2010 with a measured creatinine clearance (CrCl) of 120 mL/min or more (based on 24-hour urinary collection) were included. The measured clearance values were compared with estimated clearance values as calculated by the Cockcroft-Gault (CrCl(CG)) method and the reexpressed 4-variable Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR) formula. Spearman rank order correlation was performed to determine the relationship between measured and estimated clearances. Bland-Altman plots were evaluated to assess bias and limits of agreement between the 2 methods. RESULTS: Records on 1317 patients were screened. Augmented renal clearance was present in 390 patients. Spearman correlation showed fair correlation between measured and estimated clearances (r(s) = 0.343; p < 0.001 [CrCl(CG)] and r(s) = 0.290; p < 0.001 [eGFR]). Bias was -11.2 mL/min with limits of agreement (-131.7; 109.3 mL/min [CrCl(CG)]) and -19.9 mL/min with limits of agreement (-170.4; 130.7 mL/min [eGFR]). CONCLUSIONS: Estimated renal clearances, such as the eGFR estimated by the MDRD formula or CrCl estimated by CG, showed poor agreement with measured CrCl values in our critically ill population displaying augmented renal clearance. Clinicians should be cautious when interpreting kidney function based on estimating equations in this subset of patients. Instead, measured CrCl using urinary collection is recommended in patients suspected of displaying augmented renal clearance.

Stability of therapeutic albumin solutions used for molecular adsorbent recirculating system-based liver dialysis.

Mounting evidence suggests beneficial effects of albumin dialysis-based liver support in patients suffering from acute-on-chronic liver failure. Molecular adsorbent recirculating system (MARS) is a nonbiological liver support device, based on the exchange of albumin-bound toxins between the patient's blood and a 20% human serum albumin solution in a secondary circuit. Bound toxins are continuously removed from the circulating albumin by exposure to activated charcoal and an ion-exchange resin. The aim of the present in vitro study was to determine the impact of exposure to charcoal and resin on the ligand binding properties of albumins, containing various levels of stabilizers and obtained from different suppliers (Baxter, CAF-DCF [Red Cross], and Sigma-Aldrich). Albumin binding properties were assessed by measuring equilibrium binding properties of warfarin, diazepam, and salicylate before and after incubation (for up to 7 h) with adsorbing materials; albumin-associated esterase-like activities were also determined. Notable changes in albumin binding upon incubation with adsorbing materials were only observed when using warfarin as a ligand. Affinity of warfarin for the Baxter and Sigma albumins showed a pronounced decrease (higher K(d) ) after the 1-7-h exposure to charcoal or resin. In the absence of adsorbing materials, similar effects were found, indicating that incubation time per se affects albumin binding properties. Following exposure to resin, Baxter albumin binding capacity (B(max)) increased about twofold. For albumin obtained from CAF-DCF, binding affinity and capacity for warfarin were constant under all conditions tested. Esterase-like activities associated with these albumins were either maintained or enhanced (up to 2.5-fold in case of Sigma albumin) following 7-h incubations with adsorbing materials. Our data suggest limited direct influence of the presence of stabilizers in therapeutic albumin solutions on baseline binding properties of human albumin. However, in vitro incubations of these albumins for several hours resulted in supplier-specific changes in warfarin binding, suggesting an influence of stabilizers on the stability of binding properties. Further preclinical and clinical studies are required to elucidate the clinical relevance of these in vitro results, that is, to what extent these changes in albumin binding properties result in altered performance of albumins in the secondary circuit during the MARS procedure.

The impact of a transjugular intrahepatic portosystemic shunt on the pharmacokinetics of caspofungin in a critically ill patient.

BACKGROUND: Caspofungin is the first echinocandin approved for the treatment of invasive fungal infections (IFI). As it is also well tolerated in patients with liver cirrhosis, caspofungin is an alternative for azoles in the treatment of IFI in patients with hepatic insufficiency. METHODS: We report, for the first time, the pharmacokinetics (PK) of caspofungin in a patient with Child A cirrhosis and a transjugular intrahepatic portosystemic shunt (TIPS) and compare values to previously published results. RESULTS: Caspofungin plasma levels were determined on days 14 (before TIPS reduction) and 29 (after TIPS reduction) of treatment. Troughs and peaks were 3.55 and 3.34 mg/l on day 14 and 9.28 and 9.49 mg/l on day 29, resulting in, (1) PK parameters only slightly higher than previously reported results in healthy volunteers and patients with Child A liver cirrhosis without TIPS and (2) similar exposures before versus after TIPS reduction. This limited increase in exposure is not expected to be correlated to toxicity. CONCLUSION: Caspofungin is a safe alternative for azoles when treating patients with TIPS suffering from IFI.

Empirical management of community-acquired pneumonia: impact of concurrent A/H1N1 influenza pandemic on guideline implementation.

BACKGROUND: Guideline-concordant therapies have been proven to be associated with improved health and economic outcomes in the treatment of community-acquired pneumonia (CAP). However, actual use of CAP guidelines remains poor, but using tailored interventions looks promising. Based on local observations, we assessed the impact of low-intensity interventions to improve guideline use. METHODS: Pre-and post-intervention study with segmented regression analysis in a large tertiary care centre [University Hospitals Leuven (UZL)] and a smaller secondary care control hospital [Ziekenhuis Oost-Limburg (ZOL)] from October 2007 through to June 2010 in Belgium. RESULTS: A total of 477 patients were included in UZL, with 58.5% of the patients treated according to local guidelines. Guideline adherence remained stable, but a decrease (-28.6%; P = 0.021) was observed during guideline re-introduction in October 2009. Further analysis showed a high correlation with the concurrent A/H1N1 influenza pandemic (r(point-biserial) = 0.683; P = 0.045) and with suspected influenza infection (odds ratio = 2.70; P = 0.038). In ZOL, 326 patients were enrolled, with 69.3% being treated concordantly. A similar, non-significant decrease in guideline adherence was observed after October 2009. CONCLUSIONS: Our interventions did not lead to a higher proportion of CAP patients receiving guideline-compliant therapy. Instead, a compliance decrease was observed, coinciding with the peak in the A/H1N1 pandemic in the population. Similar observations could be made in ZOL. The widespread attention for this pandemic may have altered the perception of needed antibiotic therapy for pulmonary infections, bypassing our interventions and decreasing actual guideline compliance. Increased vigilance and follow-up is needed when epidemics with similar impact occur in the future.

No interference of the 1,3-ß-D-glucan containing nutritional supplement ImunixX with the 1,3-ß-D-glucan serum test.

The detection of 1,3-ß-D-glucan serum levels may permit establishing the diagnosis of invasive fungal infections more early. We tested in six healthy volunteers whether the intake of a 1,3-ß-D-glucan-containing nutritional supplement leads to false-positive 1,3-ß-D-glucan levels. All levels were negative, even in two different dosing regimens.

Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation.

OBJECTIVES: During extracorporeal membrane oxygenation (ECMO), drug disposition changes significantly. Plasma concentrations are altered due to an expanded circulating volume leading to a decreased elimination. In addition, adsorption and sequestration of drugs by the ECMO circuit components may further alter pharmacokinetics. Treating patients during the ECMO period with antifungals is difficult. Loss in the ECMO circuit can potentially result in sub-therapeutic levels. METHODS: Two cases are presented in which caspofungin and voriconazole levels and pharmacokinetic parameters were determined during the ECMO period. RESULTS: Mean caspofungin trough and peak levels were 3.73 and 11.95 microg/mL. These are comparable to previously reported ones. Also pharmacokinetic parameters were identical to those reported in the literature. It seems that caspofungin is not sequestrated by the ECMO circuit, which is expected based on its low log P value. During the first days of ECMO therapy, voriconazole trough and peak levels did not differ much from those determined prior to ECMO therapy. However, at the start of ECMO therapy, the voriconazole dose was increased from 280 to 400 mg twice daily as loss due to binding to the circuit was expected. This increase was not immediately reflected in higher voriconazole levels, which may be due to drug sequestration by the circuit. However, the voriconazole half-life was extended up to 20 h in our patient. Two days after the dose increase, levels reached troughs >10 microg/mL and peaks of around 15 microg/mL, exceeding the therapeutic interval for voriconazole. This can possibly be explained by the saturation of binding sites on the ECMO circuit. CONCLUSIONS: Our results suggest that adequate caspofungin plasma levels are maintained during ECMO. In the case of voriconazole, it is recommended to monitor plasma levels to ensure efficacy and avoid toxicity.

Therapeutic drug monitoring of phenytoin in critically ill patients.

Therapeutic drug monitoring of phenytoin is necessary to ensure therapeutic and nontoxic levels. Hypoalbuminemia, renal failure, and interactions with other highly protein-bound drugs (e.g., valproic acid) alter protein binding of phenytoin. When these conditions are present, free serum concentrations, which represent the pharmacologically active entity, cannot be predicted from total serum concentrations. Besides general alterations in drug distribution and elimination, protein binding is often altered in critically ill patients. Case reports describe phenytoin toxicity secondary to inappropriate dosage adjustments based solely on total serum concentrations in patients with hypoalbuminemia. Free drug measurements and theoretical equations to facilitate the interpretation of total phenytoin serum levels have been introduced. However, they are not widely implemented in clinical practice because evidence of improvements in patient outcomes is limited. Knowledge of the pharmacokinetic properties of phenytoin is indispensable for correct interpretation of total serum concentrations when protein binding is altered. Free serum concentrations should be measured, or theoretically calculated if measurements are unavailable, to avoid misinterpretation of total serum levels and consequent inappropriate adjustments in the dosage of phenytoin in critically ill patients.

Interaction between valproate and meropenem: a retrospective study.

BACKGROUND: Valproate and meropenem are frequently used in the intensive care unit to treat seizures and serious infections, respectively. Several case reports have described a remarkable interaction between the drugs when administered concurrently. The interaction leads to a significant drop in plasma concentrations of valproate within 24 hours and relapse of seizures in some patients. OBJECTIVE: To evaluate a consecutive population of hospitalized patients who were simultaneously treated with meropenem and valproate and assess the effect on epileptic activity. METHODS: A retrospective study of an 18 month period was performed to assess the extent and clinical impact of this interaction. To assess the relevance of the interaction, the time-relationship between the drop in plasma concentrations and relapse in seizure activity and/or deterioration of electroencephalogram recordings was determined. We investigated other contributing proconvulsive cofactors and concomitant antiepileptic treatment. Drug interaction probability scale (DIPS) scores were calculated. RESULTS: Thirty-nine patients were treated simultaneously with valproate and meropenem. The pharmacokinetic interaction was observed in all 39 patients, with an average drop in valproate plasma concentrations of 66%. The decrease occurred within 24 hours, as shown in 19 patients who had daily plasma concentration monitoring. The clinical impact of the interaction could not be assessed in 19 (49%) patients due to death (n = 13) or incomplete charts (n = 6). In the remaining 20 (51%) patients, DIPS scores were calculated and clinical relevance was assessed. The interaction was considered to be probable in 16 patients and possible in 4, as calculated by the DIPS. The interaction contributed to electroclinical deterioration in 11 patients. CONCLUSIONS: The pharmacokinetic interaction between valproate and meropenem was present in all patients and led to a drop of valproate concentrations with an average of 66% within 24 hours. This interaction was clinically relevant with electroclinical deterioration in 55% of patients. To avoid patients' possible neurologic deterioration, meropenem and valproate should not be administered together.

Meropenem -valproic acid interaction in patients with cefepime-associated status epilepticus.

PURPOSE: Two case reports of rapid decreases in valproic acid levels after initiation of meropenem in patients who developed new-onset seizure activity during treatment with cefepime are presented. SUMMARY: A 60-year-old Caucasian woman with myelodysplasia was transferred to the medical intensive care unit (MICU) on day 11 of her hospitalization. Cefepime was given as empiric therapy for febrile neutropenia. Pulmonary invasive aspergillosis was diagnosed. On day 16 of hospitalization, epileptic activity was confirmed. Valproic acid was initiated. Cefepime was discontinued and meropenem was initiated for treatment of cefepime-resistant pneumonia. Serum valproic acid levels decreased to subtherapeutic levels within 24 hours. Meropenem was discontinued and ceftazidime was started on day 22; serum valproic acid levels gradually increased but never reached therapeutic levels again. The patient died of intractable invasive aspergillosis on day 33. A 54-year-old Caucasian man with myelodysplasia was admitted to the MICU for nonconvulsive status epilepticus. Ten days before admission, cefepime had been started empirically for the treatment of neutropenic fever. One day before MICU admission, valproic acid was initiated as treatment for status epilepticus. The next day, serum valproic acid levels were therapeutic; cefepime was switched to meropenem. Serum valproic acid levels decreased within 24 hours and phenytoin was added. On day 4, the patient's serum valproic acid levels decreased further and meropenem was discontinued. Although the valproic acid dosage was increased, valproic acid levels did not return to the therapeutic range. The patient died on day 11. CONCLUSION: Following cefepime therapy, a clinically important interaction between meropenem and valproic acid occurred in two critically ill patients with new-onset status epilepticus.